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JAC Advance Access originally published online on November 3, 2006
Journal of Antimicrobial Chemotherapy 2007 59(1):118-121; doi:10.1093/jac/dkl448
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Evaluation of 3-deaza-adenosine analogues as ligands for adenosine kinase and inhibitors of Mycobacterium tuberculosis growth

Mary C. Long1, Paula W. Allan2, Mei-Zhen Luo3, Mao-Chin Liu3, Alan C. Sartorelli3 and William B. Parker2,*

1 Department of Pharmacology and Toxicology, University of Alabama at Birmingham Birmingham, AL 35294-0019, USA 2 Biochemistry and Molecular Biology Department, Southern Research Institute, 2000 Ninth Avenue South Birmingham, AL 35205, USA 3 Department of Pharmacology, Yale University School of Medicine New Haven, CT 06520-8066, USA

Received 27 June 2006; returned 19 September 2006; revised 4 October 2006; accepted 10 October 2006

*Corresponding author. Tel: +1-205-581-2797; Fax: +1-205-581-2093; E-mail: Parker{at}SRI.org

Objectives: Analyse a series of halogenated 3-deaza-adenosine analogues for efficacy against Mycobacterium tuberculosis H37Ra and determine if adenosine (Ado) kinase plays a role in the mechanism of action of these compounds.

Methods: The MIC as determined by microdilution broth assay provided a measure of antitubercular efficacy. MIC values were measured in M. tuberculosis strains H37Ra, SRICK1 (an Ado kinase-deficient strain of M. tuberculosis derived from H37Ra) and SRICK1 complemented with adoK, the gene which codes for Ado kinase in M. tuberculosis, in order to determine if Ado kinase played a role in the mechanism of action of these compounds. Furthermore, each compound was analysed as both a substrate and inhibitor for purified Ado kinases from M. tuberculosis and human sources.

Results: 2-Fluoro-3-deaza-adenosine, 3-fluoro-3-deaza-adenosine and 2,3-difluoro-3-deaza-adenosine exhibited antitubercular activity that was Ado kinase-dependent. Furthermore, these compounds were at least 10-fold better substrates for M. tuberculosis Ado kinase than the human homologue.

Conclusions: The Ado kinase-dependent antitubercular activity exhibited by several of the halogenated 3-deaza-adenosine analogues investigated in this study warrants further investigation of these compounds as antitubercular agents. Furthermore, substrate and inhibition studies provided insight into the Ado-binding domain of Ado kinase, indicating that steric hindrance may limit the size of exocyclic modifications at the 3-position of Ado.

Keywords: nucleoside analogues , structure-activity relationship , purines , antitubercular activity , mechanism of action


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